Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

Yoonmi Lee, Nam Hee Kim, Eunae Sandra Cho, Ji Hye Yang, Yong Hoon Cha, Hee Eun Kang, Jun Seop Yun, Sue Bean Cho, Seon-Hyeong Lee, Petra Paclikova, Tomasz W. Radaszkiewicz, Vitezslav Bryja, Chi Gu Kang, Young Soo Yuk, So Young Cha, Soo-Youl Kim, Hyun Sil Kim () and Jong In Yook ()
Additional contact information
Yoonmi Lee: Yonsei University College of Dentistry
Nam Hee Kim: Oral Cancer Research Institute, Yonsei University College of Dentistry
Eunae Sandra Cho: Yonsei University College of Dentistry
Ji Hye Yang: Yonsei University College of Dentistry
Yong Hoon Cha: Yonsei University College of Dentistry
Hee Eun Kang: Yonsei University College of Dentistry
Jun Seop Yun: Yonsei University College of Dentistry
Sue Bean Cho: Oral Cancer Research Institute, Yonsei University College of Dentistry
Seon-Hyeong Lee: Cancer Cell and Molecular Biology Branch, National Cancer Center
Petra Paclikova: Institute of Experimental Biology, Faculty of Science, Masaryk University
Tomasz W. Radaszkiewicz: Institute of Experimental Biology, Faculty of Science, Masaryk University
Vitezslav Bryja: Institute of Experimental Biology, Faculty of Science, Masaryk University
Chi Gu Kang: Yonsei University College of Dentistry
Young Soo Yuk: Yonsei University College of Dentistry
So Young Cha: Yonsei University College of Dentistry
Soo-Youl Kim: Cancer Cell and Molecular Biology Branch, National Cancer Center
Hyun Sil Kim: Oral Cancer Research Institute, Yonsei University College of Dentistry
Jong In Yook: Yonsei University College of Dentistry

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity. DVL is also required for YAP subcellular localization induced by E-cadherin, α-catenin, or AMPK activation. Importantly, the nuclear-cytoplasmic trafficking is dependent on the p53-Lats2 or LKB1-AMPK tumor suppressor axes, which determine YAP phosphorylation status. In vivo and clinical data support that the loss of p53 or LKB1 relieves DVL-linked reciprocal inhibition between the Wnt and nuclear YAP activity. Our observations provide mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.

Date: 2018
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DOI: 10.1038/s41467-018-04757-w

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